FDA Warns of Liver Injury Risk with Tolvaptan

by John Gever John Gever,Senior Editor, MedPage Today
January 25, 2013

Three cases of serious but reversible increases in hepatic enzymes in a clinical trial involving tolvaptan (Samsca) have prompted the FDA to warn of potential liver injury with the drug.

Tolvaptan's manufacturer, Otsuka America Pharmaceutical, has also sent a "Dear Healthcare Provider" letter to physicians with the warning.

According to the letter, dated Jan. 22, three patients out of some 1,400 participating in a clinical trial of tolvaptan, a selective vasopressin V2-receptor antagonist, in autosomal dominant polycystic kidney disease (ADPKD) developed increases in serum alanine aminotransferase (ALT) three times above the upper limit of normal, as well as elevated serum total bilirubin above twice the upper limit of normal.

"An external panel of liver experts assessed these three cases as being either probably or highly likely to be caused by tolvaptan. These findings indicate that Samsca (tolvaptan) has the potential to cause irreversible and potentially fatal liver injury," Otsuka said in the letter.

The company indicated that all three patients improved after the drug was stopped.

Also of concern, according to Otsuka, was that the incidence of seriously elevated ALT was significantly greater with tolvaptan versus placebo in the trial. ALT increases three times above the upper limit of normal were detected in 42 of 958 patients receiving the drug, compared with five of 484 patients in the placebo group.

In these patients, "the elevations gradually improved after discontinuation of tolvaptan," Otsuka said.

Although tolvaptan is not approved for ADPKD -- its current approved indication is for treating clinically significant hypervolemic or euvolomic hyponatremia -- Otsuka and the FDA determined that the risk of liver injury seen in the trial could carry over to other patients.

Otsuka pointed out that liver enzyme elevations had not been noted in clinical trials with tolvaptan for the hyponatremia indication.

But, the company said, "these data are not adequate to exclude the possibility that patients receiving Samsca for its indicated use of clinically significant hypervolemic and euvolemic hyponatremia are at a potentially increased risk for irreversible and possibly fatal liver injury."

Patients with underlying liver disease that may cause or contribute to hyponatremia may be less able to recover from drug-induced liver injury, Otsuka said.

"Limiting the duration of Samsca therapy may reduce the risk of developing liver injury," the company suggested.

It also recommended that healthcare providers order liver tests in patients with symptoms consistent with hepatic injury. These include fatigue, anorexia, discomfort in the upper right abdomen, dark urine, or jaundice.

"If hepatic injury is suspected, Samsca should be promptly discontinued, appropriate treatment should be instituted, and investigations should be performed to determine probable cause," Otsuka said.

"Samsca should not be re-initiated in patients unless the cause for the observed liver injury is definitively established to be unrelated to treatment with Samsca."

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